Among women in the U.S., breast cancer is the most common cancer and the second-most common cause of cancer death. Estrogen Receptor (ER)-positive breast cancer is treated with agents designed to block the pro-proliferative action of the estrogen receptor. One such agent is the antiestrogen tamoxifen.
Tamoxifen itself binds very poorly to the ER. However, when activated by metabolic action, tamoxifen gives rise to derivatives that bind very tightly to the ER and put it in an inactive state that prevents it from modulating transcription of pro-proliferative genes. The tamoxifen is activated to inhibit ER action by metabolizing enzymes that convert the tamoxifen to 4-hydroxy tamoxifen (4-OHT) or to 4-hydroxy N-desmethyl tamoxifen (also known as endoxifen). These later compounds bind with high affinity to the ER, with binding constants roughly equal to that of estradiol. See Jordan, V. C., “New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer,” Steroids, vol. 72, issue 13, pp. 829-842, November 2007.
Some women have defects in the activating enzymes of tamoxifen metabolism, especially the cytochrome p450 enzyme Cyp2D6, resulting in lowered levels of active tamoxifen metabolites in their circulation. See Lim, H.-S. et al., “Clinical Implications of CYP2D6 Genotypes Predictive of Tamoxifen Pharmacokinetics in Metastatic Breast Cancer,” Journal of Clinical Oncology, vol. 25, no. 25, pp. 3837-3845, Sep. 1, 2007; Schroth, W. et al., “Breast Cancer Treatment Outcome With Adjuvant Tamoxifen Relative to Patient CYP2D6 and CYP2C19 Genotypes,” Journal of Clinical Oncology, vol. 25, no. 33, pp. 5187-5193, Nov. 20, 2007; and Kiyotani, K. et al., “Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy,” Cancer Science, Online Early Articles, pp. 1-5, published online Feb. 24, 2008. Women with such defects have a poorer response to tamoxifen therapy and reduced tumor-free survival. In contrast, women with super-fast metabolism of tamoxifen and increased endoxifen levels have a superior clinical response to tamoxifen. See Schroth, W. et al., “Breast Cancer Treatment Outcome With Adjuvant Tamoxifen Relative to Patient CYP2D6 and CYP2C19 Genotypes,” Journal of Clinical Oncology, vol. 25, no. 33, pp. 5187-5193, Nov. 20, 2007. In addition to these genetic factors, it is also known that certain drugs, especially selective serotonin reuptake inhibitors (SSRIs) such as PAXIL®, also interfere with Cyp2d6 activity including the conversion of tamoxifen to active metabolites (discussed in Jordan, V. C., “New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer,” Steroids, vol. 72, issue 13, pp. 829-842, November 2007).
The activity of tamoxifen, 4-hydroxytamoxifen, and endoxifen are affected by their rates of processing in the body. Endoxifen and 4-hydroxytamoxifen have hydroxy groups that are reported to be substrates for O-glucuronidation by two UGTs: 1A8 and 1A10. See Sun, D. et al., “Glucuronidation of Active Tamoxifen Metabolites by the Human UDP Glucuronosyltransferases,” Drug Metabolism and Disposition, vol. 35, no. 11, pp. 2006-2014, November 2007. These enzymes are present in both the gut and liver as well as other extrahepatic tissues and may possibly inactivate endoxifen by O-linked glucuronidation at the hydroxyl group. For example, it has been reported that glucuronated endoxifen can no longer bind to the ER (Zheng, Y. et al., “Elimination of Antiestrogenic Effects of Active Tamoxifen Metabolites by Glucuronidation,” Drug Metabolism and Disposition, vol. 35, no. 10, pp. 1942-1948, October 2007). Thus, the current treatment of breast cancer with tamoxifen has an uneven effect on different patients due in part to variations in the manner in which patients metabolize tamoxifen or its metabolite endoxifen.